Dissociating the Psychoactive Effects of Distinct Cannabis Compounds in the Mesocorticolimbic Circuitry

The discovery of the endocannabinoid system propelled understanding of the mechanisms of action of cannabinoid compounds. While marijuana is the most widely used illicit substance in the world, the neuropsychopharmacological mechanisms that underlie the diffuse effects of cannabis in the brain remain poorly understood. This is because marijuana smoke represents a complex mixture of chemical components, possessing dissociable psychoactive properties. Clinical evidence suggests a functional dissociation between the two main pharmacological components of cannabis, Δ9- tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Using a combination of cortical microinfusions during two emotional learning paradigms, and single-unit in vivo electrophysiological recording, we investigated the effects of phytocannabinoid compounds in emotional regulation neural circuits, specifically the nucleus accumbens shell. We report the first demonstration of hedonic properties of CBD; an effect mediated by 5-HT1A receptors, and decreased VTA dopaminergic activity. In olfactory fear conditioning, Δ9-THC potentiates and CBD attenuates emotionally salient stimuli similar to synthetic cannabinoids

A single dose of cannabidiol modulates medial temporal and striatal function during fear processing in people at clinical high risk for psychosis

Emotional dysregulation and anxiety are common in people at clinical high risk for psychosis (CHR) and are associated with altered neural responses to emotional stimuli in the striatum and medial temporal lobe. Using a randomised, double-blind, parallel-group design, 33 CHR patients were randomised to a single oral dose of CBD (600 mg) or placebo. Healthy controls (n = 19) were studied under identical conditions but did not receive any drug. Participants were scanned with functional magnetic resonance imaging (fMRI) during a fearful face-processing paradigm. Activation related to the CHR state and to the effects of CBD was examined using a region-of-interest approach. During fear processing, CHR participants receiving placebo (n = 15) showed greater activation than controls (n = 19) in the parahippocampal gyrus but less activation in the striatum. Within these regions, activation in the CHR group that received CBD (n = 15) was intermediate between that of the CHR placebo and control groups. These findings suggest that in CHR patients, CBD modulates brain function in regions implicated in psychosis risk and emotion processing. These findings are similar to those previously evident using a memory paradigm, suggesting that the effects of CBD on medial temporal and striatal function may be task independent

Psychotropic Effects of Cannabis Components on the Mesolimbic Dopaminergic System

The two most abundant phytochemical compounds in cannabis are cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC). THC is the primary psychoactive component of cannabis and is a partial CB1 receptor (CB1R) agonist. THC is believed to be responsible for the motivational and dependence-producing effects of cannabis and causes psychotomimetic and affective processing disturbances. Conversely, CBD, is non-psychoactive, acts as a 5-HT1A receptor agonist, antagonizes CB1Rs, and possesses both anti-psychotic and anxiolytic properties. The neural substrate believed to be responsible for many of the effects of cannabis is the dopaminergic, mesolimbic reward pathway which is responsible for the regulation of cognition and emotion. Specifically, the shell region of the nucleus accumbens (NASh) and the ventral tegmental area (VTA) are important brain areas involved in motivation, reward, aversion, and fear-related behavioural processing. Using a combination of behavioural, electrophysiology and molecular techniques, the first chapter evaluates the effects of direct infusions of CBD into the NASh. Intra-NASh CBD blocked the formation of fear memory through a 5-HT1A-dependent mechanism by functionally modulating the activity of neuronal activity dynamics directly in the VTA. In the second chapter, we examined the effects of THC in either the anterior NASh (aNASh), known as the “hedonic hotspot”, or posterior NASh, known to be involved in aversion. We demonstrate that aNASh THC produced rewarding behavioural effects and modulated reward salience through a µ-opioid-receptor-dependent mechanism, whereas THC in the pNASh produced aversive behavioural effects through a k-opioid-receptor-dependent mechanism. ICV infusions of THC caused aNASh MSN activity to decrease and increased the power of ɣ-oscillations on the local field potential but caused pNASh increased MSN activity and decreased the power of ɣ-oscillations on the local field potential. Finally, in the third chapter, we provide a characterization of how THC differentially regulates fear-related memory formation and cognitive processing via distinct Akt-dependent vs. GSK3-dependent signaling pathways, in the aNASh vs. pNASh, respectively. Together, these data provide a novel neuronal, molecular, behavioural and anatomical characterization of the effects of CBD and THC directly within the mesolimbic circuitry and reveals critical new insights into the mechanisms by which THC and CBD regulate affective and cognitive behaviours

Cannabinoid Transmission in the Basolateral Amygdala Modulates Prefrontal Cortex and Ventral Hippocampal Activity

The cannabinoid system is important for maintaining neuron-to-neuron communication within the mammalian brain. One of the most commonly used substances to alter the cannabinoid system is cannabis. Individuals who are exposed to cannabis report having dissociable effects; both positive and negative. High amounts of THC have been commonly associated with the negative effects of cannabis, whereas CBD can be used to counter these. Pre-clinical evidence suggests that the combination of the two compounds can produce a therapeutic benefit for individuals who are susceptible to the effects of THC. The present study investigates whether the combination of THC+CBD can prevent electrophysiological changes induced by THC. Using In Vivo electrophysiology, simultaneous recordings of single unit activity both in the ventral hippocampal and prefrontal cortex were compared after infusions of cannabinoids into the basolateral amygdala. THC induced changes in the PFC to increase overall activity whereas the combined dose of THC+CBD returned cortical activity to baseline and introduced a potential benefit in reduced hippocampal activity

Phytocannabinoids as novel therapeutic agents in CNS disorders

The Cannabis sativa herb contains over 100 phytocannabinoid (pCB) compounds and has been used for thousands of years for both recreational and medicinal purposes. In the past two decades, characterisation of the body's endogenous cannabinoid (CB) (endocannabinoid, eCB) system (ECS) has highlighted activation of central CB1 receptors by the major pCB, Δ9-tetrahydrocannabinol (Δ9-THC) as the primary mediator of the psychoactive, hyperphagic and some of the potentially therapeutic properties of ingested cannabis. Whilst Δ9-THC is the most prevalent and widely studied pCB, it is also the predominant psychotropic component of cannabis, a property that likely limits its widespread therapeutic use as an isolated agent. In this regard, research focus has recently widened to include other pCBs including cannabidiol (CBD), cannabigerol (CBG), Δ9tetrahydrocannabivarin (Δ9-THCV) and cannabidivarin (CBDV), some of which show potential as therapeutic agents in preclinical models of CNS disease. Moreover, it is becoming evident that these non-Δ9-THC pCBs act at a wide range of pharmacological targets, not solely limited to CB receptors. Disorders that could be targeted include epilepsy, neurodegenerative diseases, affective disorders and the central modulation of feeding behaviour. Here, we review pCB effects in preclinical models of CNS disease and, where available, clinical trial data that support therapeutic effects. Such developments may soon yield the first non-Δ9-THC pCB-based medicines

Review: The Efficacy of Cannabidiol (CBD) as Potential Antipsychotic Medication

Psychotic disorders such as schizophrenia are widespread and severely disabling; however, current pharmacological treatments are unsatisfactory due to major side effects. The current review discusses the therapeutic potential of cannabidiol (CBD), a non-psychoactive component of cannabis, as an antipsychotic drug. Research lines including studies based on animal models of psychosis, human experimental studies, neuroimaging studies, epidemiological studies, and clinical studies are reviewed. The studies described provide empirical support for the antipsychotic effects of CBD and indicate reduced side effects, high tolerability, and superior cost-effectiveness compared to regular antipsychotic medication. It is concluded that CBD may prove a safe and attractive alternative treatment for psychotic conditions. However, current evidence largely stems from experimental, non-clinical studies. Large-scale randomized clinical trials are needed before this can be implemented in practice

Characterizing the Cognitive and Emotional Effects of delta-9-Tetrahydrocannabinol in Distinct Hippocampal Sub-Regions

The objective of this study is to determine the potential differential effects of THC in the DH or VH sub-regions, as well as the upstream effects on PFC neuronal activity and oscillations. Rodents used for electrophysiology were infused with THC or vehicle in the DH or VH regions, combined with PFC recordings. Additionally, a battery of behavioural paradigms was performed. Deficits in short-term memory when THC was infused into both regions was observed, however working memory was impaired with VH infusions only. This could be due to THC-induced dysregulation in the PFC, as beta oscillations were significantly decreased selectively in the VH. Additionally, a selective increase in anxiety-related behaviours was observed following VH THC infusions, but not in the DH, which could be related to changes in ERK 1/2. These findings have implications for how marijuana may differentially impact emotional vs. cognitive functions through differential effects on hippocampal sub-regions

Effects of Cannabis sativa extract on haloperidol-induced catalepsy and oxidative stress in the mice

Haloperidol is a classic antipsychotic drug known for its propensity to cause extrapyramidal symptoms due to blockade of dopamine D2 receptors in the striatum. Interest in medicinal uses of cannabis is growing. Cannabis sativa has been suggested as a possible adjunctive in treatment of Parkinson's disease. The present study aimed to investigate the effect of repeated administration of an extract of Cannabis sativa on catalepsy and brain oxidative stress induced by haloperidol administration in mice. Cannabis extract was given by subcutaneous route at 5, 10 or 20 mg/kg (expressed as Δ9-tetrahydrocannabinol) once daily for 18 days and the effect on haloperidol (1 mg/kg, i.p.)-induced catalepsy was examined at selected time intervals using the bar test. Mice were euthanized 18 days after starting cannabis injection when biochemical assays were carried out. Malondialdehyde (MDA), reduced glutathione (GSH) and nitric oxide (the concentrations of nitrite/nitrate) were determined in brain and liver. In saline-treated mice, no catalepsy was observed at doses of cannabis up to 20 mg/kg. Mice treated with haloperidol at the dose of 1 mg/kg, exhibited significant cataleptic response. Mice treated with cannabis and haloperidol showed significant decrease in catalepsy duration, compared with the haloperidol only treated group. This decrease in catalepsy duration was evident on days 1-12 after starting cannabis injection. Later the effect of cannabis was not ap-parent. The administration of only cannabis (10 or 20 mg/kg) decreased brain MDA by 17.5 and 21.8 %, respectively. The level of nitric oxide decreased by 18 % after cannabis at 20 mg/kg. Glucose in brain decreased by 20.1 % after 20 mg/kg of cannabis extract. The administration of only haloperidol increased MDA (22.2 %), decreased GSH (25.7 %) and increased brain nitric oxide by 44.1 %. The administration of cannabis (10 or 20 mg/kg) to haloperidol-treated mice resulted in a significant decrease in brain MDA and nitric oxide as well as a significant increase in GSH and glucose compared with the haloperidol-control group. Cannabis had no significant effects on liver MDA, GSH, nitric oxide in saline or haloperidol-treated mice. It is concluded that cannabis improves catalepsy induced by haloperidol though the effect is not maintained on repeated cannabis administration. Cannabis alters the oxidative status of the brain in favor of reducing lipid peroxidation, but reduces brain glucose, which would impair brain energetics

Towards a healthier cannabis? Examining neurobehavioural interactions between THC and CBD in mice

Abstract Cannabis is the most widely used illicit drug in the world, however over the past decade there has been increasing interest in its utility as a potential therapeutic. Despite the reported beneficial effects of cannabis constituent Δ9-tetrahydrocannabinol (THC), its psychoactivity has curtailed its therapeutic use. There has been increasing interest in combining non-psychoactive cannabis constituent cannabidiol (CBD with THC to inhibit THC’s adverse effects, leading to generation of medications which contain ~1:1 CBD to THC dose ratios which are currently used for the treatment of spasticity in multiple sclerosis and pain relief. However there is a limited evidence base regarding to what extent CBD might modulate the pharmacological effects of THC at equal doses. The scientific examination of pharmacological interactions between these chemicals is therefore of major medical and public health significance. This thesis examines whether an equivalent dose of CBD is able to ameliorate the neuropharmacological effects of THC in mice following acute and repeated dosing in adulthood and adolescence, using doses relevant to human consumption. We report that CBD acutely inhibited some (but not all) of the neurobehavioural measures taken, suggesting potential benefits of CBD in reducing the unwanted effects of THC. However, the unexpected activation of mesolimbic circuitry when THC and CBD were combined suggests enthusiasm should be tempered until these effects are better understood. Adolescent mice exposed to a modest THC dose equivalent to most recreational and medicinal users did not display long-term behavioural deficits, and hence no reversal of negative outcomes by CBD could be measured. CBD alone produced no behavioural changes following acute or repeated exposure in adult mice, although adolescent CBD exposure reduced depression-like behaviour in adult mice, an intriguing effect warranting further study

The acute effects of cannabidiol on the neural correlates of reward anticipation and feedback in healthy volunteers

Background: Cannabidiol has potential therapeutic benefits for people with psychiatric disorders characterised by reward function impairment. There is existing evidence that cannabidiol may influence some aspects of reward processing. However, it is unknown whether cannabidiol acutely affects brain function underpinning reward anticipation and feedback. Hypotheses: We predicted that cannabidiol would augment brain activity associated with reward anticipation and feedback. Methods: We administered a single 600 mg oral dose of cannabidiol and matched placebo to 23 healthy participants in a double-blind, placebo-controlled, repeated-measures design. We employed the monetary incentive delay task during functional magnetic resonance imaging to assay the neural correlates of reward anticipation and feedback. We conducted whole brain analyses and region-of-interest analyses in pre-specified reward-related brain regions. Results: The monetary incentive delay task elicited expected brain activity during reward anticipation and feedback, including in the insula, caudate, nucleus accumbens, anterior cingulate and orbitofrontal cortex. However, across the whole brain, we did not find any evidence that cannabidiol altered reward-related brain activity. Moreover, our Bayesian analyses showed that activity in our regions-of-interest was similar following cannabidiol and placebo. Additionally, our behavioural measures of motivation for reward did not show a significant difference between cannabidiol and placebo. Discussion: Cannabidiol did not acutely affect the neural correlates of reward anticipation and feedback in healthy participants. Future research should explore the effects of cannabidiol on different components of reward processing, employ different doses and administration regimens, and test its reward-related effects in people with psychiatric disorders